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Abstract:

Disclosed are compounds having the formula: or a salt thereof, wherein A,
n, R1, R1A, and R2 are as defined herein, and methods of
making and using the same.
##STR00001##

Claims:

1-35. (canceled)

36. A compound according to Formula (I): ##STR00288## wherein: R1A
is H, fluoro, methyl, methoxy or ethoxy; n is 1, 2 or 3; each R1 is
independently selected from halogen, hydroxy, (C1-C6)alkyl,
cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C4
alkyl)(C1-C4 alkyl)amino-halo(C2-C6)alkyl,
(C1-C4 alkyl)(C1-C4 alkyl)amino-, --ORx,
--SO2Rx, --NRzSO2Rx, (C1-C4
alkyl)(C1-C4 alkyl)amino-SO2NRz--,
--CONRyRz, --SO2NRyRz,
--SO2-heterocycloalkyl, heterocycloalkyl, and wherein any of said
heterocycloalkyl (that is, the heterocycloalkyl group and the
heterocycloalkyl moiety of the --SO2 heterocycloalkyl group) is a
4-7 membered non-aromatic ring containing one heteroatom selected from N,
O and S, or containing one nitrogen atom and one additional heteroatom
selected from N, O and S; which heterocycloalkyl is optionally
substituted by 1-5 substituents independently selected from halogen,
(C1-C6)alkyl, halo(C1-C4)alkyl,
--CO(C1-C6)alkyl, amino(C1-C4)alkyl-,
(C1-C4 alkyl)amino(C1-C4)alkyl-, (C1-C4
alkyl)(C1-C4 alkyl)amino(C1-C4)alkyl- and oxo,
Rx is selected from (C1-C6)alkyl,
halo(C1-C6)alkyl, hydroxy(C2-C6)alkyl-,
(C3-C7)cycloalkyl, amino(C2-C6)alkyl-,
((C1-C4)alkyl)amino(C2-C6)alkyl-, and
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C6)alk-
yl-, Ry is selected from H, (C1-C6)alkyl,
(C1-C6)alkoxy, (C3-C7)cycloalkyl,
amino(C2-C6)alkyl-,
((C1-C4)alkyl)amino(C2-C6)alkyl-, and
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C6)alk-
yl-, and Rz is H or (C1-C6)alkyl; or one of R1A, taken
together with an adjacent R1 group and the carbon atoms connecting
the R1A and R1 groups form a 5-6 membered, aromatic or
non-aromatic heterocyclic ring containing 1 or 2 heteroatom ring moieties
independently selected from --NR1n--, --O--, --S-- and --SO2--,
or two adjacent R1 groups taken together with the carbon atoms
connecting the two groups form a 5-6 membered, aromatic or non-aromatic
heterocyclic ring containing 1 or 2 heteroatom ring moieties
independently selected from --NR1n--, --O--, --S-- and --SO2--,
where R1n is H or --SO2(C1-C4 alkyl); R2 is H or
(C1-C4)alkyl; A is: ##STR00289## wherein: R3 is H,
(C1-C4)alkyl or an optionally substituted phenyl or 5-6
membered heteroaryl, where said phenyl or heteroaryl is optionally
substituted by 1-3 groups independently selected from halogen, hydroxy,
amino, C1-C3 alkyl, haloC1-C3 alkyl, C1-C3
alkoxy, haloC1-C3 alkoxy, (C1-C3)alkylamino- and
((C1-C3)alkyl)((C1-C3)alkyl)amino; each Z1,
Z2, Z3, and Z4 is independently selected from CH and
CR4; any one or two of Z1, Z2, Z3, and Z4 is N,
and each of the remaining two or three of Z1, Z2, Z3, and
Z4 is independently selected from CH and CR4, or any one of
Z1, Z2, Z3, and Z4 is NO, and each of the remaining
three of Z1, Z2, Z3, and Z4 is independently selected
from CH and CR4, where each R4 is independently selected from
halogen, (C1-C4)alkyl, halo(C1-C4)alkyl,
(C1-C4)alkoxy, phenyl-oxy, and phenyl(C1-C4)alkoxy,
wherein the phenyl moiety of said phenyl-oxy or
phenyl(C1-C4)alkoxy is optionally substituted by 1-3
independently selected (C1-C3)alkyl groups; provided that the
compound is not:
N2-(3-{[2-(diethylamino)ethyl]oxy}phenyl)-N-(4-fluoro-2H-indazol-3-y-
l)-2,4-pyrimidinediamine; or
N2-[3-{[2-(diethylamino)ethyl]oxy}-4-(methyloxy)phenyl]-N4-(4-f-
luoro-2H-indazol-3-yl)-2,4-pyrimidinediamine; or a salt thereof.

37. A compound according to Formula (I-B): wherein: ##STR00290## n is
1, 2 or 3; R1 is halogen, (C1-C6)haloalkoxy,
--ORx--SO2Rx, --SO2NRxRy or
heterocycloalkyl, wherein said heterocycloalkyl is a 5-6 membered
non-aromatic ring containing one heteroatom selected from N, O and S, or
containing one nitrogen atom and optionally containing 1 additional
heteroatom selected from N, O and S; which is optionally substituted by
1-5 substituents independently selected from (C1-C6)alkyl,
(C1-C4)haloalkyl, --CO(C1-C6)alkyl,
aminoC1-C4 alkyl-, (C1-C4 alkyl)aminoC1-C4
alkyl-, (C1-C4 alkyl)(C1-C4
alkyl)aminoC1-C4 alkyl-, and oxo; and wherein each Rx and
Ry are independently selected from H, (C1-C6 alkyl),
(C3-C7)cycloalkyl, amino(C2-C6 alkyl)-,
(C1-C4 alkyl)amino(C2-C6 alkyl)-, and
(C1-C4 alkyl)(C1-C4 alkyl)amino(C2-C6
alkyl)-, or Rx and Ry taken together with the nitrogen atom to
which they are attached form a 4-7 membered non-aromatic heterocyclic
ring optionally containing 1 additional heteroatom selected from N, O and
S; which is optionally substituted by 1-5 substituents independently
selected from (C1-C6)alkyl, (C1-C4)haloalkyl,
--CO(C1-C6)alkyl, amino(C1-C4 alkyl)-,
(C1-C4 alkyl)amino(C1-C4 alkyl)-, (C1-C4
alkyl)(C1-C4 alkyl)amino(C1-C4 alkyl)-, and oxo;
R2 is H or (C1-C4)alkyl; A is: ##STR00291## wherein:
R3 is H, (C1-C4)alkyl or an optionally substituted phenyl
or 5-6 membered heteroaryl, where said phenyl or heteroaryl is optionally
substituted by 1-3 groups independently selected from halogen, hydroxy,
amino, C1-C3 alkyl, haloC1-C3 alkyl, C1-C3
alkoxy, haloC1-C3 alkoxy, (C1-C3)alkylamino- and
((C1-C3)alkyl)((C1-C3)alkyl)amino; each Z1,
Z2, Z3, and Z4 is independently selected from CH and
CR4; or any one or two of Z1, Z2, Z3, and Z4 is
N, and each of the remaining two or three of Z1, Z2, Z3,
and Z4 is independently selected from CH and CR4, where each
R4 is independently selected from halogen, C1-C4 alkyl,
C1-C4 alkoxy, and phenylC1-C4 alkoxy; provided that
the compound is not:
N2-(3-{[2-(diethylamino)ethyl]oxy}phenyl)-N'-(4-fluoro-2H-indazol-3--
yl)-2,4-pyrimidinediamine; or
N2-[3-{[2-(diethylamino)ethyl]oxy}-4-(methyloxy)phenyl]-N'-(4-fluoro-
-2H-indazol-3-yl)-2,4-pyrimidinediamine; or a salt thereof.

38. The compound or salt according to claim 36, wherein R1A is H.

39. The compound or salt according to claim 36, wherein R1A taken
together with an adjacent R1 group form a --CH═CH2S-- or a
--CH═CH2NH-- moiety or two adjacent R1 groups form a
--SO2CH═CH2--, --OCH2CH2O--,
--CH2CH2O--, --CH═CH2NH-- or a
--CH═CH2N(SO2CH3)-- moiety.

40. The compound or salt according to claim 36, wherein each R1 is
independently selected from halogen, (C1-C4)alkoxy,
--SO2(C1-C4)alkyl, --SO2NRyRz, and an
optionally substituted 6-membered non-aromatic heterocyclic ring
containing one heteroatom selected from N, O and S, or containing one
nitrogen atom and optionally containing 1 additional heteroatom selected
from N, O and S, where said heterocyclic ring is optionally substituted
one or two times, independently, by (C1-C6)alkyl, wherein
Ry and Rz are each independently selected from H and
(C1-C4 alkyl) or Ry is H, (C1-C2 alkyl), or
(C1-C2 alkyl)(C1-C2 alkyl)amino(C2-C3
alkyl)- and Rz is H or (C1-C2 alkyl), or Ry and
Rz, taken together are --CH2CH2CH2CH.sub.2--.

43. The compound or salt according to claim 36, wherein n is 2 or 3 and
each R1 is independently selected from (C1-C4)alkoxy.

44. The compound or salt according to claim 36, wherein R2 is H or
R2 is methyl.

45. The compound or salt according to claim 36, wherein R3 is H or
R3 is methyl.

46. The compound or salt according to claim 36, wherein: each of Z1,
Z2, Z3, and Z4 are CH; or one of Z1, Z2,
Z3, and Z4 is CR4 and the remaining three of Z1,
Z2, Z3, and Z4 are CH; or two of Z1, Z2,
Z3, and Z4 are CR4 and the remaining two of Z1,
Z2, Z3, and Z4 are CH.

47. The compound or salt according to claim 36, wherein: one of Z1,
Z2, Z3, and Z4 is N and each of the remaining three of
Z1, Z2, Z3, and Z4 are CH; or one of Z1,
Z2, Z3, and Z4 is N, another one of Z1, Z2,
Z3, and Z4 is CR4, and the remaining two of Z1,
Z2, Z3, and Z4 are CH; or one of Z1, Z2,
Z3, and Z4 is N, two of the remaining Z1, Z2,
Z3, and Z4 are CR4, and the remaining Z1, Z2,
Z3, or Z4 is CH.

48. The compound or salt according to claim 36, wherein: one of Z1,
Z2, Z3, and Z4 is NO and each of the remaining three of
Z1, Z2, Z3, and Z4 are CH; or one of Z1,
Z2, Z3, and Z4 is NO, another one of Z1, Z2,
Z3, and Z4 is CR4, and the remaining two of Z1,
Z2, Z3, and Z4 are CH; or one of Z1, Z2,
Z3, and Z4 is NO, two of the remaining Z1, Z2,
Z3, and Z4 are CR4, and the remaining Z1, Z2,
Z3, or Z4 is CH.

49. The compound or salt according to claim 36, wherein each R4 is
independently selected from halogen, (C1-C2)alkyl,
halo(C1-C2)alkyl, (C1-C4)alkoxy, phenyl-oxy, and
phenyl(C1-C4)alkoxy, wherein the phenyl moiety of said
phenyl-oxy or phenyl(C1-C4)alkoxy is optionally substituted by
1 or 2 independently selected (C1-C2)alkyl groups.

50. The compound or salt according to claim 36, wherein each R4 is
independently selected from halogen, C1-C3 alkyl,
C1-C3 alkoxy, and phenylC1-C2 alkoxy.

51. The compound or salt according to claim 36, wherein each R4 is
independently selected from chloro, fluoro, methyl, and methoxy.

55. A pharmaceutical composition comprising the compound according to
claim 36, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to indazolyl-pyrimidinyl diamines
that inhibit RIP2 kinase and methods of making and using the same.
Specifically, the present invention relates to substituted indazoles as
RIP2 kinase inhibitors.

[0010] and wherein any of said heterocycloalkyl (that is, the
heterocycloalkyl group and the heterocycloalkyl moiety of the
--SO2heterocycloalkyl group) is a 4-7 membered non-aromatic ring
containing one heteroatom selected from N, O and S, or containing one
nitrogen atom and one additional heteroatom selected from N, O and S;
which heterocycloalkyl is optionally substituted by 1-5 substituents
independently selected from halogen, (C1-C6)alkyl,
halo(C1-C4)alkyl, --CO(C1-C6)alkyl,
amino(C1-C4)alkyl-, (C1-C4
alkyl)amino(C1-C4)alkyl-, (C1-C4
alkyl)(C1-C4 alkyl)amino(C1-C4)alkyl- and oxo,
Rx is selected from (C1-C6)alkyl,
halo(C1-C6)alkyl, hydroxy(C2-C6)alkyl-,
(C3-C7)cycloalkyl, amino(C2-C6)alkyl-,
((C1-C4)alkyl)amino(C2-C6)alkyl-, and
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C6)alk-
yl-,

[0013] or one of R1A, taken together with an adjacent R1 group
and the carbon atoms connecting the R1A and R1 groups form a
5-6 membered, aromatic or non-aromatic heterocyclic ring containing 1 or
2 heteroatom ring moieties independently selected from --NR1n,
--O--, --S-- and --SO2--, or two adjacent R1 groups taken
together with the carbon atoms connecting the two groups form a 5-6
membered, aromatic or non-aromatic heterocyclic ring containing 1 or 2
heteroatom ring moieties independently selected from --NR1n--,
--O--, --S-- and --SO2--, where R1n is H or
--SO2(C1-C4 alkyl);

[0017] each Z1, Z2, Z3, and Z4 is independently
selected from CH and CR4;

[0018] any one or two of Z1, Z2, Z3, and Z4 is N, and
each of the remaining two or three of Z1, Z2, Z3, and
Z4 is independently selected from CH and CR4, or

[0019] any one of Z1, Z2, Z3, and Z4 is NO, and each
of the remaining three of Z1, Z2, Z3, and Z4 is
independently selected from CH and CR4,

[0020] where each R4 is independently selected from halogen,
(C1-C4)alkyl, halo(C1-C4)alkyl,
(C1-C4)alkoxy, phenyl-oxy, and phenyl(C1-C4)alkoxy,
wherein the phenyl moiety of said phenyl-oxy or
phenyl(C1-C4)alkoxy is optionally substituted by 1-3
independently selected (C1-C3)alkyl groups;

[0029] and wherein any of said heterocycloalkyl (that is, the
heterocycloalkyl group and the heterocycloalkyl moiety of the --SO2
heterocycloalkyl group) is a 4-7 membered non-aromatic ring containing
one heteroatom selected from N, O and S, or containing one nitrogen atom
and one additional heteroatom selected from N, O and S; which
heterocycloalkyl is optionally substituted by 1-5 substituents
independently selected from halogen, (C1-C6)alkyl,
halo(C1-C4)alkyl, --CO(C1-C6)alkyl,
amino(C1-C4)alkyl-, (C1-C4
alkyl)amino(C1-C4)alkyl-, (C1-C4
alkyl)(C1-C4 alkyl)amino(C1-C4)alkyl- and oxo,

[0033] or one of R1A, taken together with an adjacent R1 group
and the carbon atoms connecting the R1A and R1 groups form a
5-6 membered, aromatic or non-aromatic heterocyclic ring containing 1 or
2 heteroatom ring moieties independently selected from --NR1n--,
--O--, --S-- and --SO2--, or two adjacent R1 groups taken
together with the carbon atoms connecting the two groups form a 5-6
membered, aromatic or non-aromatic heterocyclic ring containing 1 or 2
heteroatom ring moieties independently selected from --NR1n--,
--O--, --S-- and --SO2--, where R1n is H or
--SO2(C1-C4 alkyl);

[0037] each Z1, Z2, Z3, and Z4 is independently
selected from CH and CR4;

[0038] any one or two of Z1, Z2, Z3, and Z4 is N, and
each of the remaining two or three of Z1, Z2, Z3, and
Z4 is independently selected from CH and CR4, or

[0039] any one of Z1, Z2, Z3, and Z4 is NO(N-oxide),
and each of the remaining three of Z1, Z2, Z3, and Z4
is independently selected from CH and CR4,

[0040] where each R4 is independently selected from halogen,
(C1-C4)alkyl, halo(C1-C4)alkyl,
(C1-C4)alkoxy, phenyl-oxy, and phenyl(C1-C4)alkoxy,
wherein the phenyl moiety of said phenyl-oxy or
phenyl(C1-C4)alkoxy is optionally substituted by 1-3
independently selected (C1-C3)alkyl groups;

[0041] or a salt, particularly a pharmaceutically acceptable salt,
thereof.

[0042] The compounds of the invention (that is the compounds of Formula
(I) and (I-A), and salts thereof), are inhibitors of RIP2 kinase and can
be useful for the treatment of RIP2-mediated diseases and disorders,
particularly uveitis, dermatitis, arthritis Crohn's disease, asthma,
early-onset and extra-intestinal inflammatory bowel disease, and
granulomateous disorders, such as adult sarcoidosis, Blau syndrome,
early-onset sarcoidosis, and Wegner's Granulomatosis. Accordingly, the
invention is further directed to pharmaceutical compositions comprising a
compound of the invention.

[0043] The invention is still further directed to methods of inhibiting
RIP2 kinase and treatment of conditions associated therewith using a
compound of the invention or a pharmaceutical composition comprising a
compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0044] It will be appreciated by those skilled in the art that the
compounds of this invention, represented by generic Formula (II):

##STR00006##

exist as tautomers (where R3 is H) or regioisomers (where R3 is
alkyl or (het)aryl) of Formula (II)-A and Formula (II)-B, as follows:

##STR00007##

wherein the group A is represented as formula A-a and A-b, respectively:

##STR00008##

[0045] In addition, it will be appreciated by those skilled in the art
that the compounds of this invention may exist in several other
tautomeric forms. All tautomeric forms of the compounds described herein
are intended to be encompassed within the scope of the present invention.
It is to be understood that any reference to a named compound of this
invention is intended to encompass all tautomers of the named compound
and any mixtures of tautomers of the named compound.

[0046] The alternative definitions for the various groups and substituent
groups of Formula I provided throughout the specification are intended to
particularly describe each compound species disclosed herein,
individually, as well as groups of one or more compound species. The
scope of this invention includes any combination of these group and
substituent group definitions. The compounds of the invention are only
those which are contemplated to be "chemically stable" as will be
appreciated by those skilled in the art.

[0047] In one embodiment of the compounds of this invention, R1A is
H. In another embodiment, R1A is fluoro. In a further embodiment,
R1A is methyl. In yet another embodiment, R1A is methoxy or
ethoxy.

[0049] and wherein any of said heterocycloalkyl is a 5-6 membered
non-aromatic ring containing one heteroatom selected from N, O and S, or
containing one nitrogen atom and one additional heteroatom selected from
N, O and S; which heterocycloalkyl is optionally substituted by 1-3
substituents independently selected from halogen, (C1-C4)alkyl,
halo(C1-C4)alkyl, --CO(C1-C4)alkyl,
amino(C1-C4)alkyl-, (C1-C4
alkyl)amino(C1-C4)alkyl-, (C1-C4
alkyl)(C1-C4 alkyl)amino(C1-C4)alkyl- and oxo,

[0053] or one of R1A, taken together with an adjacent R1 group
and the carbon atoms connecting the R1A and R1 groups or two
adjacent R1 groups taken together with the carbon atoms connecting
the two R1 groups form a 6 membered, non-aromatic heterocyclic ring
containing two --O-- ring moieties or a 5 membered, aromatic or
non-aromatic heterocyclic ring containing one --NR1n--, --O--, --S--
or --SO2-- ring moiety, where R1n is H or
--SO2(C1-C4 alkyl).

[0055] and wherein any of said heterocycloalkyl is a 5-6 membered
non-aromatic ring containing one heteroatom selected from N, O and S, or
containing one nitrogen atom and one additional heteroatom selected from
N, O and S; which heterocycloalkyl is optionally substituted by 1-3
independently selected (C1-C4)alkyl substituents,

[0057] Ry is selected from H, (C1-C4)alkyl,
(C1-C4)alkoxy, and
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alk-
yl-, and

[0058] Rz is H or (C1-C4)alkyl;

[0059] or one of R1A, taken together with an adjacent R1 group
and the carbon atoms connecting the R1A and R1 groups or two
adjacent R1 groups taken together with the carbon atoms connecting
the two R1 groups form a 6 membered, non-aromatic heterocyclic ring
containing two --O-- ring moieties or a 5 membered, aromatic or
non-aromatic heterocyclic ring containing one --NR1n--, --O--, --S--
or --SO2-- ring moiety, where R1n is H or
--SO2(C1-C4 alkyl).

[0060] In another embodiment of this invention, each R1 is
independently selected from halogen, (C1-C4)alkoxy,
--SO2(C1-C4)alkyl, --SO2NRyRz, and an
optionally substituted 6-membered non-aromatic heterocyclic ring
containing one heteroatom selected from N, O and S, or containing one
nitrogen atom and optionally containing 1 additional heteroatom selected
from N, O and S, where said heterocyclic ring is optionally substituted
one or two times, independently, by (C1-C6)alkyl,

[0061] wherein Ry and Rz are each independently selected from H
and (C1-C4 alkyl) or Ry is H, (C1-C2 alkyl), or
(C1-C2 alkyl)(C1-C2 alkyl)amino(C2-C3
alkyl)- and Rz is H or (C1-C2 alkyl), or Ry and
Rz, taken together are --CH2CH2CH2CH2--.

[0063] In another embodiment of this invention, R1 is
--SO2NH2, and R1A taken together with an adjacent R1
group form a --OCH2CH2-- moiety. In a further embodiment,
R1A taken together with an adjacent R1 group form a
--CH═CH2S-- or a --CH═CH2NH-- moiety or two adjacent
R1 groups form a --SO2CH═CH2--,
--OCH2CH2O--, --CH2CH2O--, --CH═CH2NH-- or a
--CH═CH2N(SO2CH3)-- moiety.

[0064] In a further embodiment of this invention, each R1 is
independently selected from chloro, fluoro, methoxy,
--SO2(CH3), --SO2 pyrrolidin-1-yl, --SO2NH2,
--SO2N(CH3)2,
--SO2N(CH3)(CH2CH2N(CH3)2), and
4-methyl-piperazin-1-yl.

[0065] In one embodiment, n is 2 or 3 and each R1 is independently
selected from (C1-C4)alkoxy.

[0066] In another embodiment, one R1 is --SO2Rx,
--SO2NRyRz, --SO2-heterocycloalkyl or
heterocycloalkyl, wherein

[0070] any of said heterocycloalkyl is an optionally substituted 5-6
membered non-aromatic heterocyclic ring, wherein the 5 or 6-membered
non-aromatic heterocyclic ring contains one heteroatom selected from N
and O, or contains one nitrogen atom and one additional heteroatom
selected from N and O, and is optionally substituted by 1-3 independently
selected (C1-C2)alkyl substituents,

[0071] and, when n is 2 or 3, each other R1 is independently selected
from halogen, (C1-C2)alkyl, halo(C1-C2)alkyl,
(C1-C2)alkoxy, halo(C1-C2)alkoxy, and
--SO2(C1-C4)alkyl.

[0072] In yet another embodiment, n is 1, 2 or 3, one R1 is
--SO2Rx, wherein Rx is (C1-C4)alkyl,
trifluoromethyl, or hydroxy(C2-C4)alkyl-, and

[0073] when n is 2 or 3, each other R1 is independently selected from
halogen, (C1-C2)alkyl, halo(C1-C2)alkyl, hydroxy,
(C1-C2)alkoxy, halo(C1-C2)alkoxy,
--SO2(C1-C4)alkyl, --CO2(C1-C4)alkyl and an
optionally substituted 5 or 6-membered non-aromatic heterocyclic ring,
wherein the 5-6 membered non-aromatic heterocyclic ring contains one
heteroatom selected from N and O, or contains one nitrogen atom and one
additional heteroatom selected from N and O, and is optionally
substituted by 1-3 independently selected (C1-C2)alkyl
substituents.

[0074] In yet another embodiment, n is 1, 2 or 3, one R1 is
--SO2NRyRz, wherein Ry is H, (C1-C2)alkyl,
(C1-C2)alkoxy, or (C1-C2 alkyl)(C1-C2
alkyl)amino(C2-C3 alkyl)-,

[0075] and when n is 2 or 3, each other R1 is independently selected
from halogen, (C1-C2)alkyl, halo(C1-C2)alkyl, and
(C1-C2)alkoxy.

[0076] In yet another embodiment, n is 1, 2 or 3, one R1 is
--SO2-heterocycloalkyl, wherein said heterocycloalkyl is an
optionally substituted 5-6 membered non-aromatic heterocyclic ring,
wherein the 5 or 6-membered non-aromatic heterocyclic ring contains one
heteroatom selected from N and O, or contains one nitrogen atom and one
additional heteroatom selected from N and O, and is optionally
substituted by 1-3 independently selected (C1-C2)alkyl
substituents,

[0077] and when n is 2 or 3, each other R1 is independently selected
from halogen, (C1-C2)alkyl, halo(C1-C2)alkyl, and
(C1-C2)alkoxy.

[0078] In a further embodiment, n is 1 or 2 and one R1 is
heterocycloalkyl, wherein said heterocycloalkyl is an optionally
substituted 5-6 membered non-aromatic heterocyclic ring, wherein the 5 or
6-membered non-aromatic heterocyclic ring contains one heteroatom
selected from N and O, or contains one nitrogen atom and one additional
heteroatom selected from N and O, and is optionally substituted by 1-3
independently selected (C1-C2)alkyl substituents.

[0079] and when n is 2, the other R1 is independently selected from
halogen and (C1-C2)alkyl.

[0080] In specific embodiments of this invention, R2 is H or methyl.
In another specific embodiment, R2 is ethyl.

[0081] In another embodiment of this invention, R3 is H or
(C1-C4)alkyl.

[0082] In a further embodiment, R3 is an optionally substituted
phenyl or 5-6 membered heteroaryl, where said phenyl or heteroaryl is
optionally substituted by 1-2 groups independently selected from halogen,
hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy,
(C1-C3)alkylamino- and
((C1-C3)alkyl)((C1-C3)alkyl)amino, and

[0085] In specific embodiments of this invention, R3 is H or methyl.
In more specific embodiments of this invention, R3 is H.

[0086] In further embodiments, each of Z1, Z2, Z3, and
Z4 are CH.

[0087] In another embodiment, one of Z1, Z2, Z3, and
Z4 is CR4 and the remaining three of Z1, Z2, Z3,
and Z4 are CH.

[0088] In yet another embodiment, two of Z1, Z2, Z3, and
Z4 are CR4 and the remaining two of Z1, Z2, Z3,
and Z4 are CH.

[0089] In a further embodiment, three of Z1, Z2, Z3, and
Z4 are CR4 and the remaining Z1, Z2, Z3, and
Z4 is CH.

[0090] In other embodiments, one of Z1, Z2, Z3, and Z4
is N or NO and each of the remaining three of Z1, Z2, Z3,
and Z4 are CH. Specifically, Z1 is N or NO and Z2,
Z3, and Z4 are CH.

[0091] In additional embodiments, one of Z1, Z2, Z3, and
Z4 is N or NO, another one of Z1, Z2, Z3, and Z4
is CR4, and the remaining two of Z1, Z2, Z3, and
Z4 are CH. Specifically, Z1 is N or NO, any one of Z2,
Z3, or Z4 is CR4, and the other two of Z2, Z3,
and Z4 are CH. More specifically, Z1 is N or NO, Z3 is
CR4, and Z2 and Z4 are CH or Z1 is N, Z2 is
CR4, and Z3 and Z4 are CH.

[0092] In other embodiments, one of Z1, Z2, Z3, and Z4
is N or NO, two of the remaining Z1, Z2, Z3, and Z4
are CR4, and the remaining Z1, Z2, Z3, or Z4 is
CH. Specifically, Z1 is N or NO, any two of Z2, Z3, and
Z4 are CR4, and the other one of Z2, Z3, or Z4
is CH. More specifically, Z1 is N or NO, Z2 and Z3 are
CR4, and Z4 is CH.

[0093] In a further embodiment, each R4 is independently selected
from halogen, (C1-C2)alkyl, halo(C1-C2)alkyl,
(C1-C4)alkoxy, phenyl-oxy, and phenyl(C1-C4)alkoxy,
wherein the phenyl moiety of said phenyl-oxy or
phenyl(C1-C4)alkoxy is optionally substituted by 1 or 2
independently selected (C1-C2)alkyl groups.

[0094] In other embodiments, each R4 is independently selected from
halogen, C1-C3 alkyl, C1-C3 alkoxy, and
phenylC1-C2 alkoxy. In specific embodiments, each R4 is
independently selected from chloro, fluoro, methyl, trifluoromethyl,
methoxy, n-propyloxy, 3-methylphenoxy- and benzyloxy. In other specific
embodiments, each R4 is independently selected from chloro, fluoro,
methyl and methoxy. In other embodiments, each R4 is independently
selected from halogen, C1-C3 alkyl and C1-C3 alkoxy,
specifically, each R4 is independently selected from chloro, fluoro,
methyl, and methoxy.

[0095] In specific embodiments where one of Z1, Z2, Z3, and
Z4 is CR4, the remaining three of Z1, Z2, Z3,
and Z4 are CH, R4 is chloro, fluoro, methyl, methoxy, or
benzyloxy. In other specific embodiments where one of Z1, Z2,
Z3, and Z4 is CR4, the remaining three of Z1,
Z2, Z3, and Z4 are CH, R4 is chloro, fluoro, methyl,
trifluoromethyl, methoxy, or n-propoxy.

[0096] In embodiments where two of Z1, Z2, Z3, and Z4
are CR4, the other two of Z1, Z2, Z3, and Z4 are
CH, each R4 is independently selected from halogen, C1-C4
alkyl, and C1-C4 alkoxy; specifically, each R4 is
independently selected from chloro, fluoro, methyl, and methoxy. In
specific embodiments where two of Z1, Z2, Z3, and Z4
are CR4, each R4 is independently a halogen, specifically each
R4 is independently selected from chloro and fluoro or both R4
are fluoro.

[0097] In other specific embodiments where two of Z1, Z2,
Z3, and Z4 are CR4, one R4 is a halogen and the other
R4 is C1-C4 alkyl, specifically one R4 is chloro or
fluoro and the other R4 is methyl.

[0099] In other specific embodiments of this invention, A is
6-benzyloxy-1H-indazol-3-yl or 4-[(3-methylphenyl)oxy]-1H-indazol-3-yl.

[0100] In another specific embodiments of this invention, A is
1H-pyrazolo[3,4-b]pyridin-3-yl, 5-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl,
6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl,
5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl,
5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl),
5-fluoro-7-oxido-1H-pyrazolo[3,4-b]pyridin-3-yl, or
5-fluoro-6-methyl-7-oxido-1H-pyrazolo[3,4-b]pyridin-3-yl.

[0119] or a salt, particularly a pharmaceutically acceptable salt,
thereof.

[0120] The invention is further directed to a compound according to
Formula (I) or Formula (I-A), wherein R1A is H or a compound
according to Formula (I-B) wherein:

[0121] each R1 is independently selected from halogen,
(C1-C4)alkoxy, --SO2(C1-C4)alkyl,
--SO2NRyRz, and an optionally substituted 6-membered
non-aromatic heterocyclic ring containing one heteroatom selected from N,
O and S, or containing one nitrogen atom and optionally containing 1
additional heteroatom selected from N, O and S, where said heterocyclic
ring is optionally substituted one or two times, independently, by
(C1-C6)alkyl,

[0122] wherein Ry H, (C1-C2 alkyl), or (C1-C2
alkyl)(C1-C2 alkyl)amino(C2-C3 alkyl)- and Rz is
H or (C1-C2 alkyl), or Ry and Rz, taken together are
--CH2CH2CH2CH2--;

[0123] R2 is H or methyl;

[0124] R3 is H or methyl;

[0125] one of Z1, Z2, Z3, and Z4 is CR4, and
R4 is chloro, fluoro, methyl, methoxy, or benzyloxy; or two of
Z1, Z2, Z3, and Z4 are CR4, each R4 is
independently chloro or fluoro;

[0126] or a salt, particularly a pharmaceutically acceptable salt,
thereof.

[0127] The invention is further directed to a compound according to
Formula (I) or Formula (I-A), wherein R1A is H or a compound
according to Formula (I-B) wherein:

[0128] n is 1, 2 or 3;

[0129] R1 is methoxy or --SO2CH3;

[0130] R2 is H or methyl;

[0131] R3 is H or methyl;

[0132] each of Z1, Z2, Z3, and Z4 are CH, or

[0133] one of Z1, Z2, Z3, and Z4 is CR4 and the
remaining three of Z1, Z2, Z3, and Z4 are CH, or

[0134] two of Z1, Z2, Z3, and Z4 are CR4 and the
remaining two of Z1, Z2, Z3, and Z4 are CH, or
[0135] one of Z1, Z2, Z3, and Z4 is N and each of the
remaining three of Z1, Z2, Z3, and Z4 are CH, or

[0136] one of Z1, Z2, Z3, and Z4 is N, another one of
Z1, Z2, Z3, and Z4 is CR4, and the remaining two
of Z1, Z2, Z3, and Z4 are CH;

[0137] where each R4 is independently selected from chloro, fluoro,
methyl, and methoxy;

[0138] or a salt, particularly a pharmaceutically acceptable salt,
thereof.

[0139] The invention is further directed to a compound according to
Formula (I) or Formula (I-A), wherein:

[0140] R1A is H;

[0141] n is 1, 2 or 3;

[0142] one R1 is --SO2Rx, --SO2NRyRz,
--SO2-heterocycloalkyl or heterocycloalkyl, wherein

[0146] any of said heterocycloalkyl is an optionally substituted 5-6
membered non-aromatic heterocyclic ring, wherein the 5 or 6-membered
non-aromatic heterocyclic ring contains one heteroatom selected from N
and O, or contains one nitrogen atom and one additional heteroatom
selected from N and O, and is optionally substituted by 1-3 independently
selected (C1-C2)alkyl substituents,

[0147] and, when n is 2 or 3, each other R1 is independently selected
from halogen, (C1-C2)alkyl, halo(C1-C2)alkyl,
(C1-C2)alkoxy, halo(C1-C2)alkoxy, and
--SO2(C1-C4)alkyl;

[0148] R2 is H or methyl;

[0149] R3 is H or methyl;

[0150] one of Z1, Z2, Z3, and Z4 is CR4, the
remaining three of Z1, Z2, Z3, and Z4 are CH, and
R4 is chloro, fluoro, methyl, trifluoromethyl, methoxy, or
n-propoxy, or

[0151] two of Z1, Z2, Z3, and Z4 are CR4, and the
other two of Z1, Z2, Z3, and Z4 are CH, where each
R4 is independently selected from chloro and fluoro, or one R4
is a is chloro or fluoro and the other R4 is C1-C4 alkyl,
specifically one R4 is chloro or fluoro and the other R4 is
methyl.

[0152] The invention is further directed to a compound according to
Formula (I) or Formula (I-A), wherein:

[0164] As used herein, the term "alkyl" represents a saturated, straight
or branched hydrocarbon moiety, which may be unsubstituted or substituted
by one, or more of the substituents defined herein. Exemplary alkyls
include, but are not limited to methyl (Me), ethyl (Et), propyl,
isopropyl, butyl, isobutyl, t-butyl and pentyl. The term
"C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.

[0165] When the term "alkyl" is used in combination with other substituent
groups, such as "haloalkyl" or "hydroxyalkyl" or "arylalkyl", the term
"alkyl" is intended to encompass a divalent straight or branched-chain
hydrocarbon radical. For example, "arylalkyl" is intended to mean the
radical -alkylaryl, wherein the alkyl moiety thereof is a divalent
straight or branched-chain carbon radical and the aryl moiety thereof is
as defined herein, and is represented by the bonding arrangement present
in a benzyl group (--CH2-phenyl).

[0166] As used herein, the term "alkenyl" refers to a straight or branched
hydrocarbon moiety containing at least 1 and up to 3 carbon-carbon double
bonds. Examples include ethenyl and propenyl.

[0167] As used herein, the term "alkynyl" refers to a straight or branched
hydrocarbon moiety containing at least 1 and up to 3 carbon-carbon triple
bonds. Examples include ethynyl and propynyl.

[0168] As used herein, the term "cycloalkyl" refers to a non-aromatic,
saturated, cyclic hydrocarbon ring. The term
"(C3-C8)cycloalkyl" refers to a non-aromatic cyclic hydrocarbon
ring having from three to eight ring carbon atoms. Exemplary
"(C3-C8)cycloalkyl" groups useful in the present invention
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
and cyclooctyl.

[0169] "Alkoxy" refers to a group containing an alkyl radical attached
through an oxygen linking atom. The term "(C1-C4)alkoxy" refers
to a straight- or branched-chain hydrocarbon radical having at least 1
and up to 4 carbon atoms attached through an oxygen linking atom.
Exemplary "(C1-C4)alkoxy" groups useful in the present
invention include, but are not limited to, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, s-butoxy, and t-butoxy.

[0170] "Alkylthio-" refers to a group containing an alkyl radical attached
through a sulfur linking atom. The term "(C1-C4)alkylthio-"
refers to a straight- or branched-chain hydrocarbon radical having at
least 1 and up to 4 carbon atoms attached through a sulfur linking atom.
Exemplary "(C1-C4)alkylthio-" groups useful in the present
invention include, but are not limited to, methylthio-, ethylthio-,
n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and
t-butylthio-.

[0171] "Cycloalkyloxy" and "cycloalkylthio" refers to a group containing a
saturated carbocyclic ring atoms attached through an oxygen or sulfur
linking atom, respectively. Examples of "cycloalkyloxy" moieties include,
but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy,
cyclohexyloxy, and the like.

[0172] "Aryl" represents a group or moiety comprising an aromatic,
monovalent monocyclic or bicyclic hydrocarbon radical containing from 6
to 10 carbon ring atoms, which may be unsubstituted or substituted by one
or more of the substituents defined herein, and to which may be fused one
or more cycloalkyl rings, which may be unsubstituted or substituted by
one or more substituents defined herein.

[0173] Generally, in the compounds of this invention, aryl is phenyl.

[0174] Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.

[0175] "Heterocycloalkyl" represents a group or moiety comprising a
non-aromatic, monovalent monocyclic or bicyclic radical, which is
saturated or partially unsaturated, containing 3 to 10 ring atoms, which
includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur,
and which may be unsubstituted or substituted by one or more of the
substituents defined herein. Illustrative examples of heterocycloalkyls
include, but are not limited to, azetidinyl, pyrrolidyl (or
pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl,
tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl),
dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl,
dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl,
azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and
1,5,9-triazacyclododecyl.

[0179] It is to be understood that the terms heterocycle, heterocyclic,
heteroaryl, heterocycloalkyl, are intended to encompass stable
heterocyclic groups where a ring nitrogen heteroatom is optionally
oxidized (e.g., heterocyclic groups containing an N-oxide, such as
pyridine-N-oxide) or where a ring sulfur heteroatom is optionally
oxidized (e.g., heterocyclic groups containing sulfones or sulfoxide
moieties, such as tetrahydrothienyl-1-oxide (a tetramethylene sulfoxide)
or tetrahydrothienyl-1,1-dioxide (a tetramethylene sulfone)).

[0180] "Oxo" represents a double-bonded oxygen moiety; for example, if
attached directly to a carbon atom forms a carbonyl moiety (C═O). The
terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo
substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical
--OH.

[0181] As used herein, the term "compound(s) of the invention" means a
compound of Formula (I), (I-A) or (I-B) (as defined above) in any form,
i.e., any salt or non-salt form (e.g., as a free acid or base form, or as
a pharmaceutically acceptable salt thereof) and any physical form thereof
(e.g., including non-solid forms (e.g., liquid or semi-solid forms), and
solid forms (e.g., amorphous or crystalline forms, specific polymorphic
forms, solvates, including hydrates (e.g., mono-, di- and
hemi-hydrates)), and mixtures of various forms.

[0182] As used herein, the term "optionally substituted" means
unsubstituted groups or rings (e.g., cycloalkyl, heterocycle, and
heteroaryl rings) and groups or rings substituted with one or more
specified substituents.

[0397] and a salt, particularly a pharmaceutically acceptable salt,
thereof.

[0398] Representative compounds of this invention include the compounds of
Examples 1-210.

[0399] Compound names were generated using the software naming program
ACD/Name Pro V6.02 available from Advanced Chemistry Development, Inc.,
110 Yonge Street, 14th Floor, Toronto, Ontario, Canada, M5C 1T4
(http://www.acdlabs.com/). It will be appreciated by those skilled in the
art that many of the compounds of this invention, as well as compounds
used in the preparation of the compounds of Formula (I), (I-A) or (I-B)
may exist in tautomeric forms. The program used to name the compounds of
this invention will only name one of such tautomeric forms at a time. It
is to be understood that any reference to a named compound or a
structurally depicted compound is intended to encompass all tautomers of
such compounds and any mixtures of tautomers thereof. For example, the
tautomer of the compound of Example 13,
N4-(5-methoxy-2H-indazol-3-yl-N2-(3,4,5-trimethoxyphenyl)pyrimi-
dine-2,4-diamine, is intended to be encompassed by the depicted structure
of Example 13 and the name provided for that structure by the naming
program: N4-[5-(methyloxy)-1H-indazol-3-yl]-N2-[3,4,5-tris(meth-
yloxy)phenyl]-2,4-pyrimidinediamine.

[0400] The compounds according to Formula (I), (I-A) or (I-B) may contain
one or more asymmetric center (also referred to as a chiral center) and
may, therefore, exist as individual enantiomers, diastereomers, or other
stereoisomeric forms, or as mixtures thereof. Chiral centers, such as
chiral carbon atoms, may also be present in a substituent such as an
alkyl group. Where the stereochemistry of a chiral center present in a
compound of this invention, or in any chemical structure illustrated
herein, is not specified the structure is intended to encompass all
individual stereoisomers and all mixtures thereof. Thus, compounds
according to Formula (I), (I-A) or (I-B) containing one or more chiral
center may be used as racemic mixtures, enantiomerically enriched
mixtures, or as enantiomerically pure individual stereoisomers.

[0401] Individual stereoisomers of a compound according to according to
Formula (I), (I-A) or (I-B) which contain one or more asymmetric center
may be resolved by methods known to those skilled in the art. For
example, such resolution may be carried out (1) by formation of
diastereoisomeric salts, complexes or other derivatives; (2) by selective
reaction with a stereoisomer-specific reagent, for example by enzymatic
oxidation or reduction; or (3) by gas-liquid or liquid chromatography in
a chiral environment, for example, on a chiral support such as silica
with a bound chiral ligand or in the presence of a chiral solvent. The
skilled artisan will appreciate that where the desired stereoisomer is
converted into another chemical entity by one of the separation
procedures described above, a further step is required to liberate the
desired form. Alternatively, specific stereoisomers may be synthesized by
asymmetric synthesis using optically active reagents, substrates,
catalysts or solvents, or by converting one enantiomer to the other by
asymmetric transformation. When a disclosed compound or its salt is named
or depicted by structure, it is to be understood that the compound or
salt, including solvates (particularly, hydrates) thereof, may exist in
crystalline forms, non-crystalline forms or a mixture thereof. The
compound or salt, or solvates (particularly, hydrates) thereof, may also
exhibit polymorphism (i.e. the capacity to occur in different crystalline
forms). These different crystalline forms are typically known as
"polymorphs." It is to be understood that when named or depicted by
structure, the disclosed compound, or solvates (particularly, hydrates)
thereof, also include all polymorphs thereof. Polymorphs have the same
chemical composition but differ in packing, geometrical arrangement, and
other descriptive properties of the crystalline solid state. Polymorphs,
therefore, may have different physical properties such as shape, density,
hardness, deformability, stability, and dissolution properties.
Polymorphs typically exhibit different melting points, IR spectra, and
X-ray powder diffraction patterns, which may be used for identification.
One of ordinary skill in the art will appreciate that different
polymorphs may be produced, for example, by changing or adjusting the
conditions used in crystallizing/recrystallizing the compound.

[0402] Because of their potential use in medicine, the salts of the
compounds of according to Formula (I), (I-A) or (I-B) are preferably
pharmaceutically acceptable salts. Suitable pharmaceutically acceptable
salts include those described by Berge, Bighley and Monkhouse J. Pharm.
Sci (1977) 66, pp 1-19. Salts encompassed within the term
"pharmaceutically acceptable salts" refer to non-toxic salts of the
compounds of this invention.

[0403] When a compound of the invention is a base (contain a basic
moiety), a desired salt form may be prepared by any suitable method known
in the art, including treatment of the free base with an inorganic acid,
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like, or with an organic acid, such as acetic
acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid,
fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,
salicylic acid, and the like, or with a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such
as citric acid or tartaric acid, or with an amino acid, such as aspartic
acid or glutamic acid, or with an aromatic acid, such as benzoic acid or
cinnamic acid, or with a sulfonic acid, such as p-toluenesulfonic acid,
methanesulfonic acid, ethanesulfonic acid or the like.

[0406] If an inventive basic compound is isolated as a salt, the
corresponding free base form of that compound may be prepared by any
suitable method known to the art, including treatment of the salt with an
inorganic or organic base, suitably an inorganic or organic base having a
higher pKa than the free base form of the compound.

[0407] When a compound of the invention is an acid (contains an acidic
moiety), a desired salt may be prepared by any suitable method known to
the art, including treatment of the free acid with an inorganic or
organic base, such as an amine (primary, secondary, or tertiary), an
alkali metal or alkaline earth metal hydroxide, or the like. Illustrative
examples of suitable salts include organic salts derived from amino acids
such as glycine and arginine, ammonia, primary, secondary, and tertiary
amines, and cyclic amines, such as N-methyl-D-glucamine, diethylamine,
isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine,
ethanolamine, piperidine, morpholine, and piperazine, as well as
inorganic salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum, and lithium.

[0408] Certain of the compounds of this invention may form salts with one
or more equivalents of an acid (if the compound contains a basic moiety)
or a base (if the compound contains an acidic moiety). The present
invention includes within its scope all possible stoichiometric and
non-stoichiometric salt forms.

[0409] Compounds of the invention having both a basic and acidic moiety
may be in the form of zwitterions, acid-addition salt of the basic moiety
or base salts of the acidic moiety.

This invention also provides for the conversion of one pharmaceutically
acceptable salt of a compound of this invention, e.g., a hydrochloride
salt, into another pharmaceutically acceptable salt of a compound of this
invention, e.g., a sodium salt.

[0410] For solvates of the compounds of the invention, or salts thereof
that are in crystalline form, the skilled artisan will appreciate that
pharmaceutically-acceptable solvates may be formed wherein solvent
molecules are incorporated into the crystalline lattice during
crystallization. Solvates may involve nonaqueous solvents such as
ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate,
or they may involve water as the solvent that is incorporated into the
crystalline lattice. Solvates wherein water is the solvent that is
incorporated into the crystalline lattice are typically referred to as
"hydrates." Hydrates include stoichiometric hydrates as well as
compositions containing variable amounts of water. The invention includes
all such solvates.

[0411] The subject invention also includes isotopically-labeled compounds
which are identical to those recited in according to Formula (I), (I-A)
or (I-B) but for the fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass or
mass number most commonly found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as
3H, 11C, 14C, 18F, 123I or 125I.

[0412] Compounds of the present invention and pharmaceutically acceptable
salts of said compounds that contain the aforementioned isotopes and/or
other isotopes of other atoms are within the scope of the present
invention. Isotopically labeled compounds of the present invention, for
example those into which radioactive isotopes such as 3H or 14C
have been incorporated, are useful in drug and/or substrate tissue
distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e.,
14C, isotopes are particularly preferred for their ease of
preparation and detectability. 11C and 18F isotopes are
particularly useful in PET (positron emission tomography).

[0413] Because the compounds of according to Formula (I), (I-A) or (I-B)
are intended for use in pharmaceutical compositions it will readily be
understood that they are each preferably provided in substantially pure
form, for example at least 60% pure, more suitably at least 75% pure and
preferably at least 85%, especially at least 98% pure (% are on a weight
for weight basis). Impure preparations of the compounds may be used for
preparing the more pure forms used in the pharmaceutical compositions.

General Synthetic Methods

[0414] The compounds of according to Formula (I), (I-A) or (I-B) may be
obtained by using synthetic procedures illustrated in the Schemes below
or by drawing on the knowledge of a skilled organic chemist. The
synthesis provided in these Schemes are applicable for producing
compounds of the invention having a variety of different R1 and
R2 groups employing appropriate precursors, which are suitably
protected if needed, to achieve compatibility with the reactions outlined
herein. Subsequent deprotection, where needed, affords compounds of the
nature generally disclosed. While the Schemes are shown with compounds
only of according to Formula (I), (I-A) or (I-B), they are illustrative
of processes that may be used to make the compounds of the invention.

[0415] Intermediates (compounds used in the preparation of the compounds
of the invention) may also be present as salts. Thus, in reference to
intermediates, the phrase "compound(s) of formula (number)" means a
compound having that structural formula or a pharmaceutically acceptable
salt thereof.

Scheme 1

[0416] Nucleophilic aromatic substitution of 4-fluoronitroanilines with
4-methylpiperazine followed by hydrogenation of the nitro group afforded
the piperazinoanilines

##STR00011##

[0417] The requisite 2-anilinopyrimidines were prepared via displacement
of the thioether moiety of 2-(Methylthio)-4(1H)-pyrimidinone using
solvent free conditions.

##STR00012##

Scheme 2

[0418] Conversion of the 2-anilinopyrimidinones was accomplished using
POCl3 and heat.

##STR00013##

Scheme 3

[0419] Non-commercial indazoles can be prepared from the corresponding
2-fluorobenzonitriles upon heating with a source of hydrazine in an
alcohol solvent.

##STR00014##

Scheme 4

[0420] Introduction of the R5 methyl substituent can be accomplished
via methylation of the corresponding indazole.

##STR00015##

Scheme 5

[0421] Substitution of the dichloropyrimidines with aminoindazoles can be
accomplished using a variety of methods including heating in water or an
acceptable solvent via thermal conditions. Substitution of the
indazolochloropyrimidines with anilines can be accomplished using a
variety of methods including heating in NMP or an acceptable solvent via
thermal condition or μw irradiation conditions.

##STR00016##

Scheme 6

[0422] Substitution of the 4-chloropyrimidines with aminoindazoles can be
accomplished using a variety of methods including heating in NMP or an
acceptable solvent via thermal or μw irradiation. The addition of acid
may be required for unreactive substrates. A palladium mediated cross
coupling reaction can also be utilized via heating of the reactants in
dioxane in the presence of Pd(OAc)2, binap, and CsCO3.

##STR00017##

[0423] The present invention is also directed to a method of inhibiting
RIP2 kinase which comprises contacting the kinase with a compound
according to Formula (I), (I-A) or (I-B), or a salt, particularly a
pharmaceutically acceptable salt, thereof. This invention is also
directed to a method of treatment of a RIP2-mediated disease or disorder
comprising administering a therapeutically effective amount of a compound
of according to Formula (I), (I-A) or (I-B), or a salt thereof,
particularly a pharmaceutically acceptable salt thereof, to a patient,
specifically a human, in need thereof. As used herein, "patient" refers
to a human or other mammal.

[0425] Treatment of RIP2-mediated disease conditions, or more broadly,
treatment of immune mediated disease, such as, but not limited to,
allergic diseases, autoimmune diseases, prevention of transplant
rejection and the like, may be achieved using a compound of this
invention of as a monotherapy, or in dual or multiple combination
therapy, particularly for the treatment of refractory cases, such as in
combination with other anti-inflammatory and/or anti-TNF agents, which
may be administered in therapeutically effective amounts as is known in
the art. For example, the compounds of this invention may be administered
in combination with corticosteroids and/or anti-TNF agents to treat Blau
syndrome/early-onset sarcoidosis; or in combination with anti-TNF
biologics or other anti-inflammatory biologics to treat Crohn's Disease;
or in combination with low-dose corticosteroids and/or methotrexate to
treat Wegener's granulamatosis or sarcoidosis or interstitial pulmonary
disease; or in combination with a biologic (e.g. anti-TNF, anti-IL-6,
etc.) to treat rheumatoid arthritis; or in combination with anti-IL6 and
or methotrexate to treat ICE fever.

[0427] This invention also provides a compound of according to Formula
(I), (I-A) or (I-B), or a salt thereof, particularly a pharmaceutically
acceptable salt thereof, for use in the treatment or prophylaxis of
RIP2-mediated diseases or disorders, for example those diseases and
disorders mentioned hereinabove.

[0428] The invention also provides the use of a compound of according to
Formula (I), (I-A) or (I-B), or a salt thereof, particularly a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the treatment or prophylaxis of RIP2-mediated diseases or
disorders, for example those diseases and disorders mentioned
hereinabove.

[0429] A therapeutically "effective amount" is intended to mean that
amount of a compound that, when administered to a patient in need of such
treatment, is sufficient to effect treatment, as defined herein. Thus,
e.g., a therapeutically effective amount of a compound of according to
Formula (I), (I-A) or (I-B), or a pharmaceutically acceptable salt
thereof, is a quantity of an inventive agent that, when administered to a
human in need thereof, is sufficient to modulate or inhibit the activity
of RIP2 kinase such that a disease condition which is mediated by that
activity is reduced, alleviated or prevented. The amount of a given
compound that will correspond to such an amount will vary depending upon
factors such as the particular compound (e.g., the potency (pIC50),
efficacy (EC50), and the biological half-life of the particular
compound), disease condition and its severity, the identity (e.g., age,
size and weight) of the patient in need of treatment, but can
nevertheless be routinely determined by one skilled in the art. Likewise,
the duration of treatment and the time period of administration (time
period between dosages and the timing of the dosages, e.g.,
before/with/after meals) of the compound will vary according to the
identity of the mammal in need of treatment (e.g., weight), the
particular compound and its properties (e.g., pharmaceutical
characteristics), disease or condition and its severity and the specific
composition and method being used, but can nevertheless be determined by
one of skill in the art.

[0430] "Treating" or "treatment" is intended to mean at least the
mitigation of a disease condition in a patient. The methods of treatment
for mitigation of a disease condition include the use of the compounds in
this invention in any conventionally acceptable manner, for example for
prevention, retardation, prophylaxis, therapy or cure of a mediated
disease. Specific diseases and conditions that may be particularly
susceptible to treatment using a compound of this invention are described
herein.

[0431] The compounds of the invention may be administered by any suitable
route of administration, including both systemic administration and
topical administration. Systemic administration includes oral
administration, parenteral administration, transdermal administration,
rectal administration, and administration by inhalation. Parenteral
administration refers to routes of administration other than enteral,
transdermal, or by inhalation, and is typically by injection or infusion.
Parenteral administration includes intravenous, intramuscular, and
subcutaneous injection or infusion. Inhalation refers to administration
into the patient's lungs whether inhaled through the mouth or through the
nasal passages. Topical administration includes application to the skin.

[0432] The compounds of the invention may be administered once or
according to a dosing regimen wherein a number of doses are administered
at varying intervals of time for a given period of time. For example,
doses may be administered one, two, three, or four times per day. Doses
may be administered until the desired therapeutic effect is achieved or
indefinitely to maintain the desired therapeutic effect. Suitable dosing
regimens for a compound of the invention depend on the pharmacokinetic
properties of that compound, such as absorption, distribution, and
half-life, which can be determined by the skilled artisan. In addition,
suitable dosing regimens, including the duration such regimens are
administered, for a compound of the invention depend on the condition
being treated, the severity of the condition being treated, the age and
physical condition of the patient being treated, the medical history of
the patient to be treated, the nature of concurrent therapy, the desired
therapeutic effect, and like factors within the knowledge and expertise
of the skilled artisan. It will be further understood by such skilled
artisans that suitable dosing regimens may require adjustment given an
individual patient's response to the dosing regimen or over time as
individual patient needs change.

[0433] For use in therapy, the compounds of the invention will be
normally, but not necessarily, formulated into a pharmaceutical
composition prior to administration to a patient. Accordingly, the
invention is also directed to pharmaceutical compositions comprising a
compound of the invention and a pharmaceutically-acceptable excipient.

[0434] The pharmaceutical compositions of the invention may be prepared
and packaged in bulk form wherein an effective amount of a compound of
the invention can be extracted and then given to the patient such as with
powders, syrups, and solutions for injection. Alternatively, the
pharmaceutical compositions of the invention may be prepared and packaged
in unit dosage form. For oral application, for example, one or more
tablets or capsules may be administered. A dose of the pharmaceutical
composition contains at least a therapeutically effective amount of a
compound of this invention (i.e., a compound of according to Formula (I),
(I-A) or (I-B) or a salt, particularly a pharmaceutically acceptable
salt, thereof). When prepared in unit dosage form, the pharmaceutical
compositions may contain from 1 mg to 1000 mg of a compound of this
invention.

[0435] The pharmaceutical compositions of the invention typically contain
one compound of the invention. However, in certain embodiments, the
pharmaceutical compositions of the invention contain more than one
compound of the invention. In addition, the pharmaceutical compositions
of the invention may optionally further comprise one or more additional
pharmaceutically active compounds.

[0436] As used herein, "pharmaceutically-acceptable excipient" means a
material, composition or vehicle involved in giving form or consistency
to the composition. Each excipient must be compatible with the other
ingredients of the pharmaceutical composition when commingled such that
interactions which would substantially reduce the efficacy of the
compound of the invention when administered to a patient and interactions
which would result in pharmaceutical compositions that are not
pharmaceutically-acceptable are avoided. In addition, each excipient must
of course be of sufficiently high purity to render it
pharmaceutically-acceptable.

[0437] The compounds of the invention and the pharmaceutically-acceptable
excipient or excipients will typically be formulated into a dosage form
adapted for administration to the patient by the desired route of
administration. Conventional dosage forms include those adapted for (1)
oral administration such as tablets, capsules, caplets, pills, troches,
powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and
cachets; (2) parenteral administration such as sterile solutions,
suspensions, and powders for reconstitution; (3) transdermal
administration such as transdermal patches; (4) rectal administration
such as suppositories; (5) inhalation such as aerosols and solutions; and
(6) topical administration such as creams, ointments, lotions, solutions,
pastes, sprays, foams, and gels.

[0438] Suitable pharmaceutically-acceptable excipients will vary depending
upon the particular dosage form chosen. In addition, suitable
pharmaceutically-acceptable excipients may be chosen for a particular
function that they may serve in the composition. For example, certain
pharmaceutically-acceptable excipients may be chosen for their ability to
facilitate the production of uniform dosage forms. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to
facilitate the production of stable dosage forms. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to
facilitate the carrying or transporting the compound or compounds of the
invention once administered to the patient from one organ, or portion of
the body, to another organ, or portion of the body. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to
enhance patient compliance.

[0439] Suitable pharmaceutically-acceptable excipients include the
following types of excipients: diluents, fillers, binders, disintegrants,
lubricants, glidants, granulating agents, coating agents, wetting agents,
solvents, co-solvents, suspending agents, emulsifiers, sweeteners,
flavoring agents, flavor masking agents, coloring agents, anti-caking
agents, humectants, chelating agents, plasticizers, viscosity increasing
agents, antioxidants, preservatives, stabilizers, surfactants, and
buffering agents. The skilled artisan will appreciate that certain
pharmaceutically-acceptable excipients may serve more than one function
and may serve alternative functions depending on how much of the
excipient is present in the formulation and what other ingredients are
present in the formulation.

[0440] Skilled artisans possess the knowledge and skill in the art to
enable them to select suitable pharmaceutically-acceptable excipients in
appropriate amounts for use in the invention. In addition, there are a
number of resources that are available to the skilled artisan which
describe pharmaceutically-acceptable excipients and may be useful in
selecting suitable pharmaceutically-acceptable excipients. Examples
include Remington's Pharmaceutical Sciences (Mack Publishing Company),
The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and
The Handbook of Pharmaceutical Excipients (the American Pharmaceutical
Association and the Pharmaceutical Press).

[0441] The pharmaceutical compositions of the invention are prepared using
techniques and methods known to those skilled in the art. Some of the
methods commonly used in the art are described in Remington's
Pharmaceutical Sciences (Mack Publishing Company).

[0442] In one aspect, the invention is directed to a solid oral dosage
form such as a tablet or capsule comprising an effective amount of a
compound of the invention and a diluent or filler. Suitable diluents and
fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch
(e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose
and its derivatives (e.g. microcrystalline cellulose), calcium sulfate,
and dibasic calcium phosphate. The oral solid dosage form may further
comprise a binder. Suitable binders include starch (e.g. corn starch,
potato starch, and pre-gelatinized starch), gelatin, acacia, sodium
alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and
its derivatives (e.g. microcrystalline cellulose). The oral solid dosage
form may further comprise a disintegrant. Suitable disintegrants include
crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and
sodium carboxymethyl cellulose. The oral solid dosage form may further
comprise a lubricant. Suitable lubricants include stearic acid, magnesium
stearate, calcium stearate, and talc.

EXAMPLES

[0443] The following examples illustrate the invention. These examples are
not intended to limit the scope of the present invention, but rather to
provide guidance to the skilled artisan to prepare and use the compounds,
compositions, and methods of the present invention. While particular
embodiments of the present invention are described, the skilled artisan
will appreciate that various changes and modifications can be made
without departing from the spirit and scope of the invention.

[0444] Names for the intermediate and final compounds described herein
were generated using a software naming program. It will be appreciated by
those skilled in the art that in certain instances this program will name
a structurally depicted compound as a tautomer of that compound. It is to
be understood that any reference to a named compound or a structurally
depicted compound is intended to encompass all tautomers of such
compounds and any mixtures of tautomers thereof. the following
experimental descriptions, the following abbreviations may be used:

[0445] In the following experimental descriptions, the following
abbreviations may be used:

[0447] A mixture of 1-methylpiperazine (35.5 g, 354 mmol) and
1-fluoro-4-nitrobenzene (10 g, 70.9 mmol) was heated in a sealed tube at
100° C. for 20 hours. The reaction was cooled to rt. Cold water
was added and the resulting solid was collected via filtration, washing
with water, then air dried to give the title compound as an orange solid
15.4 g.

(4-Aminophenyl)[2-(dimethylamino)ethyl]ethylamine

##STR00019##

[0449] 1-Methyl-4-(4-nitrophenyl)piperazine (7.7 g, 34.8 mmol) was
dissolved in MeOH (200 mL) and Pd/C (0.185 g, 1.740 mmol) was added. The
reaction mixture was placed under an atmosphere of H2 for 24 hour.
The reaction was filtered through a pad of celite, washed with MeOH,
concentrated and dried on high vacuum to give the product as a brown
solid 6.6 g.

[0451] 3-bromo-5-methylbenzenesulfonyl chloride (3 g, 11.13 mmol) was
dissolved in MeOH (20 mL) and ammonia in MeOH (9.54 mL, 66.8 mmol) was
added dropwise and an exotherm was noted. The reaction was stirred for
one hour and LCMS analysis (A1) showed the reaction was complete. The
solvent was removed and the resulting residue dissolved in MeOH,
concentrated onto silica, and purified via flash chromatography using a
100 g SNAP cartridge eluting with 0-100% EtOAc/hexanes to give the
desired product as a white solid (2.1 g, 74%). The product was then added
to a solution of N,N-dimethylformamide dimethyl acetal (5.54 ml, 41.4
mmol) in N,N-Dimethylformamide (DMF) (6.28 ml) and the reaction was
stirred at rt for one hour. Water (2 mL) was added and the mixture was
stirred for several minutes then filtered washing with water. The
resulting solid was dried on the vacuum funnel (2.4 g, 95%). The solid
was placed in a flask along with PdOAc2 (0.088 g, 0.393 mmol), xantphos
(0.455 g, 0.786 mmol), and cesium carbonate (7.69 g, 23.59 mmol). To the
mixture was added 1,4-Dioxane (24.23 ml) followed by benzophenone imine
(1.979 ml, 11.80 mmol). The reaction was degassed by bubbling through
N2 for several minutes, then was heated to 95° C. for 5
hours. The reaction was filtered through celite washing with MeOH then
concentrated onto silica and purified via flash chromatography eluting
with 30-50% EtOAc/hexanes for 30 min then 100% EtOAc for 20 min. The
product was recrystallized from EtOAc to give the title compound as a
yellow solid (1.34 g). The solid was a 1:1 mixture of product and
benzophenone imine byproduct. 1H NMR (DMSO-d6) δ: 8.05
(s, 1H), 7.63-7.69 (m, 2H), 7.52-7.58 (m, 1H), 7.45-7.51 (m, 2H),
7.30-7.37 (m, 3H), 7.10-7.18 (m, 3H), 6.80 (s, 1H), 6.76 (s, 1H), 3.14
(s, 3H), 2.86 (s, 3H), 2.24 (s, 3H); MS (m/z) 242 (M+H.sup.+).

Preparation 3

2-fluoro-3-(methylsulfonyl)aniline

##STR00021##

[0453] A solution of 1-bromo-2-fluorobenzene (310 μl, 2.86 mmol) in
Tetrahydrofuran (THF) (1.21E+04 μl) was cooled to -78° C. and
treated with LDA (1571 μl, 3.14 mmol) and stirred for 20 min. Then
dimethyldisulfide (330 μl, 3.71 mmol) was added and the reaction was
allowed to slowly warmed to rt overnight. LCMS showed a peak at 1.01 min,
but the mass didn't match the product. The crude mixture was quenched
with 10% H2SO4 and the layers were separated and the aqueous layer
extracted with EtOAc. The combined extracts were washed with satd aq
NaHCO3, dried over MgSO4, filtered, and concentrated onto silica. The
crude product was purified via flash chromatography using a 25 g column
eluting with 0-100% EtOAc/hexanes. The product was dissolved in
Dichloromethane (DCM) (1.07E+04 μl) and treated with MCPBA (779 mg,
4.51 mmol). The reaction was stirred for one hour at rt then 1 mL of DMF
was added and the reaction was stirred over the weekend at rt. The
reaction was concentrated onto silica and purified via flash
chromatography using a 25 g column eluting with 0-100% EtOAc/hexanes. The
product eluted was a mixture of 3-chlorobenzoic acid and product based on
NMR analysis. The sample was dissolved in EtOAc and washed with 2×
satd aq NaHCO3 and the organic solution was dried over MgSO4, filtered,
and concentrated to an orange oil (422 mg, 78%). The oil was then
combined with Pd2(dba)3 (79 mg, 0.086 mmol), xantphos (100 mg, 0.173
mmol), cesium carbonate (844 mg, 2.59 mmol), and tert-butyl carbamate
(303 mg, 2.59 mmol). 1,4-Dioxane (5756 μl) was added and the solution
was degassed with N2. The reaction was then heated to 100° C. for
20 hours. The reaction was filtered then concentrated and the resulting
residue was dissolved in DCM. The solution was filtered then treated with
TFA (2.5 mL) and the reaction was stirred at rt for 2 hours. The reaction
was then concentrated onto silica and the crude material was purified via
flash chromatography using a 40 g column eluting with 0-100%
EtOAc/hexanes to give the title compound as a brown oil (132 mg, 40%).
1H NMR (DMSO-d6) δ: 7.05-7.16 (m, 2H), 6.93 (dt, J=6.0,
2.9 Hz, 1H), 3.26 (s, 3H); MS (m/z) 190 (M+H.sup.+).

[0466] The following intermediates, used for the preparation of named
example compounds, were synthesized using methods analogous to the ones
described above.

##STR00029##

Preparation 9

1-(methyloxy)-3-(methylsulfonyl)-5-nitrobenzene

##STR00030##

[0468] To a magnetically stirred solution of
1-(ethyloxy)-3-(methylsulfonyl)-5-nitrobenzene (277 mg, 1.129 mmol) in
Acetic Acid (3 mL) at room temperature was added zinc (378 mg, 5.78 mmol)
in one portion. The reaction stirred at room temperature for 1 hour. The
mixture was diluted with EtOAc and then filtered through Celite. The
solution was diluted with water and neutralized through the addition of
solid K2CO3. The layers were separated and the organic layer
was concentrated under reduced pressure to give
[3-(ethyloxy)-5-(methylsulfonyl)phenyl]amine (111 mg, 0.516 mmol, 45.7%
yield) which was carried on without further purification. MS (m/z) 216
(M+H.sup.+).

[0469] The following intermediates, used for the preparation of named
example compounds, were synthesized using methods analogous to the ones
described above.

##STR00031##

Preparation 10

4-(ethyloxy)-3-[(1-methylethyl)sulfonyl]aniline

##STR00032##

[0471] To a mixture of sodium bicarbonate (318 mg, 3.78 mmol) and sodium
sulfite (454 mg, 3.60 mmol) in Water (33 mL) was added a solution of
5-(acetylamino)-2-(ethyloxy)benzenesulfonyl chloride (500 mg, 1.800 mmol)
in Ethanol (0.65 μl). The reaction was heated to 50° C. for one
hour then concentrated. The resulting residue was dissolved in
N,N-Dimethylformamide (DMF) (4901 μl) and 2-iodopropane (180 μl,
1.800 mmol) was added and the reaction stirred at rt for 16 hours. The
solution was diluted with EtOAc and washed three times with satd aq
NH4Cl, dried over Na2SO4, filtered, and concentrated. The resulting
residue was dissolved in a solution of 4 N hydrochloric acid in
1,4-dioxane (202 μl, 0.806 mmol) and was heated to 100° C. for
6 hours. Water was added to the reaction and it was heated to 100°
C. for 3 hours then stirred at rt for 16 hours. The reaction was diluted
with DCM and neutralized with satd aq NaHCO3. The organic solution was
passed through a phase separator and concentrated. The material was
dissolved in MeOH and passed through an SCX cartridge washing with MeOH.
The product was eluted with a solution of 2 N NH3 in MeOH to give the
title compound as a yellow film (60 mg, 31%). 1H NMR (DMSO-d6)
δ: 7.04-7.09 (m, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.81-6.88 (m, 1H),
5.28 (br. s., 2H), 4.03 (q, J=7.0 Hz, 2H), 3.60-3.74 (m, 1H), 1.27-1.33
(m, 3H), 1.15 (d, J=6.8 Hz, 6H).

[0475] A solution of 1-(methyloxy)-3-(methylsulfonyl)-5-nitrobenzene
(435.0 mg, 1.881 mmol) in 6.0 mL of a solution of HBr in Acetic acid (40%
w/w) was heated at 90.0° C. in an oil bath. The reaction mixture
was poured onto solid ice then the aqueous suspension was extracted with
EtOAc. The organic layer was washed with sat.aq NaHCO3, dried over
sodium sulfate, filtered then concentrated. The residue was purified by
FCC using a Biotage unit [EtOAc-Hex: 10 to 40%] to yield the title
compound (191.0 mg, 46.7%). MS (m/z): 218.0 (M+H.sup.+).

Preparation 13

1-[(difluoromethyl)oxy]-3-(methylsulfonyl)-5-nitrobenzene

##STR00035##

[0477] To a solution of 3-(methylsulfonyl)-5-nitrophenol (66.0 mg, 0.304
mmol) in DMF (2.5 mL) was added potassium carbonate (147 mg, 1.064 mmol).
The mixture was stirred for 20 min at rt then methyl
chloro(difluoro)acetate (0.081 mL, 0.760 mmol) was added and the rm was
heated to 90° C.

[0480] To a solution of
1-[(difluoromethyl)oxy]-3-(methylsulfonyl)-5-nitrobenzene (110.0 mg,
0.412 mmol) in 4 mL ethyl acetate-ethanol (3:1) was added Pd/C (10% w/w)
(43.8 mg, 0.041 mmol). The mixture was stirred under hydrogen gas which
was supplied from a balloon. After 4 h the rm was filtered then
concentrated in-vacuo to yield the title compound. MS (m/z): 238.1
(M+H.sup.+).

Preparation 15

2,2,2-trifluoro-1-(3-nitrophenyl)ethanamine

##STR00037##

[0482] 2,2,2-trifluoro-1-(3-nitrophenyl)ethanone (5.00 g, 22.82 mmol) was
dissolved in toluene (30 mL) at room temperature. A solution of 1M LiHMDS
in THF (25.6 mL, 25.6 mmol) was added into the reaction solution slowly
over 10 min period of time. The mixture was stirred at room temperature
for 15 min, then BH3.DMS (4.40 mL, 46.3 mmol) was added. The
reaction mixture was stirred at room temperature for 2 h. The reaction
mixture was then quenched with Ice-water mixture. The quenched reaction
mixture was partitioned between water and dichloromethane. The organic
layer was washed by brine, dried over MgSO4, filtered, and
concentrated to about 10 ml of the toluene solution. A solution of 3 ml
4N HCl in dioxane was added dropwise. The resulting white precipitate was
collected by filtration, and then was dried under high vacuum for 16 h to
give the desired product as a white solid (5.3 g, 91% yield). 1H NMR
(400 MHz, DMSO-d6) δ: 8.40 (dd, J=8.2, 1.4 Hz, 1H), 8.17 (d,
J=7.8 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.05 (m, 1H), 5.87 (m, 1H), 3.89
(s, 2H); MS (m/z) 221 (M+H.sup.+).

Preparation 16

2,2,2-trifluoro-N,N-dimethyl-1-(3-nitrophenyl)ethanamine

##STR00038##

[0484] 2,2,2-trifluoro-1-(3-nitrophenyl)ethanamine (1 g, 4.54 mmol) was
dissolved in formic acid (3484 μl, 91 mmol) at room temperature.
Paraformaldehyde (546 mg, 18.17 mmol) was added to the reaction mixture,
and then the mixture was stirred at 100° C. for 3 h. The reaction
mixture was added into 150 ml of sat. Na2CO3(aq) slowly, and
then was extracted by dichloromethane. The organic layer was washed by
brine, dried over MgSO4 and concentrated to a brown oil. The crude
oil was purified by Isco Combiflash (5%-20% EtOAc/Hexane; 40 g column).
Collected fractions were combined and concentrated to give the desired
product as a colorless oil (600 mg, 53% yield). MS (m/z) 221 (M+H.sup.+).

[0506] The following intermediates, used for the preparation of named
example compounds, were synthesized using methods analogous to the ones
described above.

##STR00052##

Preparation 24

1-[2-methyl-3-(methylsulfonyl)-5-nitrophenyl]pyrrolidine

##STR00053##

[0508] A mixture of 1-fluoro-2-methyl-3-(methylsulfonyl)-5-nitrobenzene
(92.0 mg, 0.394 mmol), and pyrrolidine (140 mg, 1.972 mmol) were heated
at 100.0° C. for 30 min. The rm was cooled to rt then quenched
with cold water. The suspended solid was collected by filtration then
purified by FCC using a Biotage unit [EtOAc-Hex: 10-35%] to yield the
title compound (57.0 mg, 51.0%). MS (m/z) 285.2 (M+H.sup.+).

[0509] The following intermediates, used for the preparation of named
example compounds, were synthesized using methods analogous to the ones
described above.

[0523] 2,4-dichloropyrimidine (541 mg, 3.63 mmol) and
5-fluoro-N-methyl-1H-indazol-3-amine (500 mg, 3.03 mmol) were mixed in
Water (30 mL) and heated at 50° C. for 20 hours and a thick
precipitate was present. To the mixture was added 0.5 mL 2M HCl in
diethyl ether and it was stirred for 2 hours. The reaction was cooled to
room temperature and the solid was filtered, rinsing with water, and
dried in vacuum oven to give the title compound as a light yellow solid
(650 mg, 63% yield, 92% purity).

[0524] The following intermediates, used for the preparation of named
example compounds, were synthesized using methods analogous to the one
described above.

[0553] A fluorescent polarization based binding assay was developed to
quantitate interaction of novel test compounds at the ATP binding pocket
of RIPK2, by competition with a fluorescently labeled ATP competitive
ligand. Full length FLAG His tagged RIPK2 was purified from a Baculovirus
expression system and was used at a final assay concentration of twice
the KDapparent. A fluorescent labeled ligand
(5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)ph-
enyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9--
yl)benzoic acid, prepared as described below) was used at a final assay
concentration of 5 nM. Both the enzyme and ligand were prepared in
solutions in 50 mM HEPES pH7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, and 1
mM CHAPS. Test compounds were prepared in 100% DMSO and 100 nL was
dispensed to individual wells of a multiwell plate. Next, 5 ul RIPK2 was
added to the test compounds at twice the final assay concentration, and
incubated at room temperature for 10 minutes. Following the incubation, 5
ul of the fluorescent labeled ligand solution, was added to each
reaction, at twice the final assay concentration, and incubated at room
temperature for at least 10 minutes. Finally, samples were read on an
instrument capable of measuring fluorescent polarization. Test compound
inhibition was expressed as percent (%) inhibition of internal assay
controls.

[0554] For concentration response experiments, normalized data were fit
and pIC50 s determined using conventional techniques. For example,
the following four parameter logistic equation may be used:
y=A+((B-C))/(1+(10x)/(10C)D), where: y is the % activity
(% inhibition) at a specified compound concentration; A is the minimum %
activity; B is the maximum % activity; C=log10(IC50); D=Hill
slope; x=log10 (compound concentration [M]); and pIC50=(--C).

[0555] The pIC50s are averaged to determine a mean value, for a
minimum of 2 experiments. As determined using the above method, the
compounds of Examples 1-210 exhibited a pIC50 greater than or equal
to 6.0. For instance, the compounds of Example 12 and Example 27
inhibited RIP2 kinase in the above method with a mean pIC50 of 8.1
and 7.3 respectively.

FLAG His Tagged RIPK2 Preparation:

[0556] Full-length human RIPK2 (receptor-interacting serine-threonine
kinase 2) cDNA was purchased from Invitrogen (Carlsbad, Calif., USA,
Clone ID:IOH6368, RIPK2-pENTR 221). Gateway® LR cloning was used to
site-specifically recombine RIPK2 downstream to an N-terminal FLAG-6His
contained within the destination vector pDEST8-FLAG-His6 according to the
protocol described by Invitrogen. Transfection into Spodoptera
frugiperda(Sf9) insect cells was performed using Cellfectin®
(Invitrogen), according to the manufacturer's protocol.

[0557] Sf9 cells were grown in Excell 420 (SAFC Biosciences, Lenexa,
Kans., US; Andover, Hampshire UK) growth media at 27° C., 80 rpm
in shake flask until of a sufficient volume to inoculate a bioreactor.
The cells were grown in a 50 litre working volume bioreactor (Applikon,
Foster City, Calif., US; Schiedam, Netherlands) at 27° C., 30%
dissolved oxygen and an agitation rate of 60-140 rpm until the required
volume was achieved with a cell concentration of approximately 3.7xe6
cells/ml. The insect cells were infected with Baculovirus at a
multiplicity of infection (MOI) of 12.7. The cultivation was continued
for a 43 hour expression phase. The infected cells were removed from the
growth media by centrifugation at 2500 g using a Viafuge (Carr)
continuous centrifuge at a flow rate of 80 litres/hour. The cell pellet
was immediately frozen and subsequently supplied for purification.

[0573] The efficacy of the RIP2 inhibitors of this invention may also be
evaluated in vivo in rodents. Intraperitoneal (i.p.) or intravenous
(i.v.) administration of L18-MDP in mice has been shown to induce an
inflammatory response through activation of the NOD2 signaling pathway
(Rosenweig, H. L., et al. 2008. Journal of Leukocyte Biology 84:529-536).
The level of the inflammatory response in the L18-MDP treated mice/rats
is monitored using conventional techniques by measuring increases in
cytokine levels (IL8, TNFα, IL6 and IL-1β) in serum and/or
peritoneal lavage fluid and by measuring neutrophil influx into the
peritoneal space (when L18-MDP is dosed i.p.). Inhibition of the L18-MDP
induced inflammatory response in treated rodents may be shown by orally
pre-dosing with selected compounds of this invention, then measuring and
comparing cytokine levels (IL8, TNFα, IL6 and IL-1β) in serum
and/or peritoneal lavage fluid and neutrophil influx into the peritoneal
space (when L18-MDP is dosed i.p.) using conventional techniques.

Patent applications by Adam Kenneth Charnley, Collegeville, PA US

Patent applications by Ami Lakdawala Shah, King Of Prussia, PA US

Patent applications by Clark A. Sehon, King Of Prussia, PA US

Patent applications by Daohua Zhang, Collegeville, PA US

Patent applications by Jae U. Jeong, Collegeville, PA US

Patent applications by Jianxing Kang, Collegeville, PA US

Patent applications by Lara Kathryn Leister, Collegeville, PA US

Patent applications by Linda N. Casillas, Collegeville, PA US

Patent applications by Pamela A. Haile, King Of Prussia, PA US

Patent applications by Robert W. Marquis, Jr., Collegeville, PA US

Patent applications by Terry Vincent Hughes, Collegeville, PA US

Patent applications in class Three or more ring hetero atoms in the bicyclo ring system

Patent applications in all subclasses Three or more ring hetero atoms in the bicyclo ring system